Viral and bacterial infections are major causes of morbidity and mortality in humans, accounting for a third of the deaths that occur globally each year. Certain infectious agents also cause cancer and are thought to be associated with other chronic diseases such as encephalitis and meningitis. The direct healthcare cost and indirect productivity cost associated with these diseases are very high, and affect the population disproportionately. Often, viral and bacterial infections can reach epidemic proportions in poor countries and can result in large number of deaths. Both prophylactic and therapeutic interventions are important in preventing or controlling the onslaught of infectious agents. In this respect, agents that might act as immune boosters, preferably through aiding both humoral and innate immunity, are of high importance as immune adjuvants and prophylactics.
Research suggests that cancer is an inflammatory disease often driven by the lack of sufficient immune response to check the growth and propagations of malignant cells. Thus, the lack of an adequate immune response can play a central role in all aspects of cancer growth and metastases. The relevance of the role of the immune system has been clinically validated by the clinical success and the recent approval of checkpoint inhibitors and other immuno-oncology drugs. Novel immune modulators may be effective in treating various types of cancer, and may overcome deficiencies the current checkpoint inhibitors have. Recently, cyclic dinucleotides have emerged as powerful immune modulators through their binding and activation of an endoplasmic reticulum bound protein called STING, an acronym for STimulator of INterferon Genes.
Cyclic guanosine adenosine monophosphate synthase (cGAS) is the principal pattern recognition receptor that senses pathogenic versus self DNA in the cytosol and catalyzes the production of cyclic Guanosine Adenosine MonoPhosphate (cGAMP), one of the endogenous cyclic dinucleotides (Sun, L. et al. Science 2013, 339, 786-791) that serves as a second messenger to activate innate immune responses (Jiaxi Wu et al. Science 2013, 339, 826-830). The mechanism by which cGAMP activates the immune response is through its binding to the endoplasmic reticulum bound protein STING (G. N. Barber, Immunol. Rev. 2011, 243, 99) and its activation. STING activation triggers a downstream signaling cascade that results in activation of cytosolic kinases IKK (I-kappa-B Kinase) and TBK1 (TANK Binding Kinase 1), which activates the transcription factors NF-kB (Nuclear Factor kappa light chain enhancer of activated B cells) and IRF3 (Interferon Regulatory Factor 3), respectively. Translocation of NF-kB and IRF3 to the nucleus leads to the induction of type I interferons. Type I interferon induction has functional consequences for the treatment of cancer, viral diseases and bacterial infections. Following examples of STING modulators, specifically STING agonists, described in the art mainly concern 1) cancer immunotherapy and 2) anti-viral therapy. However, STING modulators may be useful in treating many types of autoimmune diseases, inflammatory conditions and bacterial infections, as will be described in the present disclosure.
Cancer Immunotherapy: Many recent high impact publications have underscored the effectiveness of STING activation as a non-specific cancer immunotherapy paradigm, and its translational capability has been highlighted. For example, Fu et al. found that co-administration of cyclic dinucleotides with a cellular cancer vaccine called STINGVAX was effective against multiple types of tumors in mouse models. Furthermore, they showed that stronger STING binding through chemical modification of CDNs increased antitumor activity (Science Translational Medicine, 2015, 7, pp. 283ra52). Another report by Corrales et al. demonstrated that intra-tumoral injection of CDNs activated STING-interferon-cytotoxic T-cell pathway and induced profound regression of established tumors in mice, and generated substantial systemic immune responses capable of rejecting distant metastases and providing long-lived immunologic memory (Cell Reports, 2015, 11, 1-13). According to these authors, “synthetic CDNs have high translational potential as a cancer therapeutic.” The emerging field of CDN based cancer immunotherapy has great potential not only as cancer vaccine adjuvants, but also as powerful cancer drugs in combination with checkpoint inhibitors. However, checkpoint inhibitors are not universally effective; they are not very effective in tumors where the immune system fail to recognize cancer cells as dangerous. But, combining checkpoint inhibitors and STING agonists have proven to be effective in killing even distant metastases (Science Translational Medicine, 2015, 7, pp. 283ra52). The present disclosure addresses these previous problems in the art and is in part directed towards CDNs acting as powerful anticancer immune stimulants, either alone or in combinations with other immuno-oncology therapeutics and/or chemotherapeutics, and/or DNA hypomethylating agents.
Anti-Viral Therapy using STING Agonists—Treating HBV infection as an example: Chronic hepatitis B virus (HBV) infection is notoriously difficult to treat, let alone cure, in spite of a number of nucleoside analogues (Nucs) available in the market. Long term treatment with Nucs and interferon is known to have therapeutic effect. However, HBV surface antigen (HBsAg) seroconversion, the sign of a successful immunologic control of HBV, or a “functional cure,” is rarely achieved with the current therapies. With over 400 million people chronically infected with HBV worldwide, the number of cases of liver fibrosis, cirrhosis and hepatocellular carcinoma resulting from long term infection is rising at an alarming rate. Thus, there is a need for effective anti HBV therapy that is robust and sustainable enough to clear the host incorporated viral genome. Recent reports suggest (Guo F, et al. Antimicrob Agents Chemother. 2015, 59, 1273-81) that the restoration of host innate and HBV-specific adaptive immune responses may be essential for a functional cure of chronic HBV infection (Chang J, et al. Antiviral Res 96:405-413).
Chronic HBV infection results from failed immune response to the onset of HBV infection. Typically, pathogen associated molecular patterns (PAMP) are sensed by host mediated pattern recognition receptors (PRRS) and puts up a strong immune response. But HBV has been shown to induce negligible innate immune responses during the early phase of infection. In fact, Type I interferon (IFN), a hallmark of antiviral innate signaling, is either undetectable or missing in most cases of HBV patients, and there is no concrete evidence that IFNs are produced in HBV patients (Dunn C, et al. Gastroenterology 2009, 137, 1289-1300). Yet, evidence suggests that HBV is sensitive to ligand mediated activation of STING-IFN pathway, and resulting antiviral response is strong and sustainable (Guo F, et al. Antimicrob Agents Chemother. 2015, 59, 1273-81). Another report has revealed that STING is a new target of the viral polymerase to antagonize the IFN induction against HBV (Liu Y, et al. J. Virol. 2015, 89, 2287-2300). When this is coupled with the fact that STING agonists induce an innate antiviral immune response against HBV, it may be possible that a viral polymerase inhibitor such as ribavirin or entecavir or any other Nucs and a CDN might have the double effect of stopping replication and providing immune boost through STING activation. From a clinical perspective, it is possible to ‘sandwich’ a STING agonist treatment with Nuc therapy that clears most of the virus, followed by STING therapy effectively clearing HBV cccDNA (covalently closed circular DNA) (interferon is produced in the nucleus), which will again be followed by nuc therapy to clear any mature virus that may have entered the cytosol. In another aspect, a CDN STING agonist can be specifically and selectively delivered to liver cells, thus restricting the systemic effect of the drug. This approach can achieve two objectives: 1) decreased toxicity to other healthy organs due to decreased dose and 2) improved efficacy due to selective delivery to hepatocytes, the host cells of HBV.
The present disclosure is intended to provide novel STING agonists/modulators as prophylactics and/or therapeutics in the treatment of cancers, viral diseases and bacterial infections.